TheAlternaria toxins alternariol (AOH), alternariol-9-methyl ether (AME), altenuene (ALT) and isoaltenuene (iALT) undergo extensive oxidative metabolism, but the cytochrome P450 (CYP) isoforms responsible for the reported hydroxylation reactions are yet unknown. In the present study, the activities of twelve human CYP isoforms for the hydroxylation of AOH, AME, ALT and iALT at different positions have been determined. The most active monooxygenase for AOH and AME was CYP1A1, and lower activities were observed for CYP1A2, 2C19 and 3A4. Hydroxylation at C-2 of AOH and AME was the preferred reaction of most isoforms. For ALT and iALT, CYP2C19 had the highest activity, followed by 2C9 and 2D6. The dominating metabolite of all active isoforms was the 8-hydroxylated ALT and iALT. The activities of the CYP isoforms are consistent with the pattern of metabolites of theAlternaria toxins obtained with pooled human hepatic microsomes. Based on the activities of the CYP isoforms, a significant extrahepatic hydroxylation must be expectede.g. in the lung and esophagus for AOH and AME, and in the intestine and ovaries for ALT and iALT. As all major hydroxylation products are catechols, the extrahepatic metabolism ofAlternaria toxins may be of toxicological relevance.

中文翻译：

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人重组细胞色素 P450 亚型和人肝微粒体对链格孢毒素羟基化的活性。

交链格孢毒素交链孢菌素 (AOH)、交链孢菌素-9-甲基醚 (AME)、交替烯 (ALT) 和异烯 (iALT) 进行广泛的氧化代谢，但导致报道的羟基化反应的细胞色素 P450 (CYP) 异构体尚不清楚。在本研究中，已经确定了 12 种人类 CYP 异构体在不同位置对 AOH、AME、ALT 和 iALT 进行羟基化的活性。AOH 和 AME 最活跃的单加氧酶是 CYP1A1，而 CYP1A2、2C19 和 3A4 的活性较低。AOH 和 AME 的 C-2 处的羟基化是大多数同工型的首选反应。对于ALT和iALT，CYP2C19的活性最高，其次是2C9和2D6。所有活性异构体的主要代谢物是 8-羟基化 ALT 和 iALT。CYP 同种型的活性与用汇集的人肝微粒体获得的链格孢属毒素的代谢物模式一致。根据 CYP 同工型的活性，必须预期有明显的肝外羟基化作用。在肺和食道中检测 AOH 和 AME，在肠道和卵巢中检测 ALT 和 iALT。由于所有主要的羟基化产物都是儿茶酚，因此链格孢属毒素的肝外代谢可能具有毒理学意义。